Incobotulinum Toxin-A in Professional Musicians with Focal Task-Specific Dystonia: A Double Blind, Placebo Controlled, Cross-Over Study

Background: Musician’s focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers. Methods: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment. Findings: 19 men and 2 women with musicians’ dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found. Interpretation: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians’ task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians’ dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer’s cramp, and spasmodic dysphonia.

Table 7: Primary Efficacy endpoint: Dynamometer measures at the eight-week mark in the active arm compared to the baseline rating.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: There were 34 dynamometer measures, among the 21 patients, only 16 patients had available rating data.
There was significant reduction from baseline rating for 11 measures in active arm compared to placebo group.Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: There were 19 pairs (left and right digit 2,3,4,5) of muscle strength based on raw data for MRC scale, most of scores were 5, so it is hardly find the difference.Method 2: Only cycle 1 was included in the analysis.
No significant change could be found.

Table 9：Secondary endpoint VAS：
Two patients ("MD103-D-M" "MD107-J-E") with outliers, could you please double check to let me know whether the drug had latter effect for them, or they were data issues?Take "MD107-J-E" as an example, took active drug in the first cycle and placebo in the second cycle, while there was no change in the first cycle, there was significant reduction in the second cycle (week 20).If these two patients were excluded from analysis, there was significant reduction in VAS score in the active group compared to placebo group.
For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for VAS scale via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find the significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: The analysis result was based on the data in which Two patients ("MD103-D-M" "MD107-J-E") with outliers were removed.(Change: post-baseline -baseline)

Table 10: Secondary Efficacy Endpoint ModHAD：
Scoring the HADS: -The "A" components are the "anxiety" components.
-The "D" components are the "depression" components.
-Total score 0-7 = normal; 8-10 = borderline; 11-21 = abnormal For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for ModHAD (both A and D components) via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find the significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.
Endpoint  Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress.►Scores ranging from 0-13 would be considered low stress.►Scores ranging from 14-26 would be considered moderate stress.►Scores ranging from 27-40 would be considered high perceived stress.
For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for PSS via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find the significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: There were 34 dynamometer measures, among the 21 patients, only 16 patients had available rating data.
There was significant reduction from baseline rating for 11 measures in active arm compared to placebo group.Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: There were 19 pairs (left and right digit 2,3,4,5) of muscle strength based on raw data for MRC scale, most of scores were 5, so it is hardly finding the difference.No significant change could be found.

Table 9: Secondary endpoint VAS：
For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5 (week 12, the start of 2 nd injection cycle) for VAS scale via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find a significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit.Note: The analysis result was based on the data in which Two patients ("MD103-D-M" "MD107-J-E") with outliers were removed.-The "A" components are the "anxiety" components.
-The "D" components are the "depression" components.
-Total score 0-7 = normal; 8-10 = borderline; 11-21 = abnormal For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for ModHAD (both A and D components) via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find the significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit  Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress.►Scores ranging from 0-13 would be considered low stress.►Scores ranging from 14-26 would be considered moderate stress.►Scores ranging from 27-40 would be considered high perceived stress.
For the AP group (took active injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for PSS via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated), we could not find the significant difference between visit 1 and visit 5.
Method 1: Assumed that the injection effect is no more than 8 weeks, so the visit 1(day 0) and visit 5(week 12, the start of 2 nd injection cycle) were considered baseline visit

Table 1 : Patient disposition and assignment to Active or Placebo arms
Active drug; P: Placebo.Note: AP: Received the active drug injection in cycle 1 and placebo in cycle 2. PA: Received the placebo in cycle 1 and active drug injection in cycle 2.

Table 2 : Demographic and Baseline Characteristics of Patients
Median total dose in the PA arm was 115 units, and in the AP arm 81.3 units, due to an outlier effect of one patient (a Rock drummer) who received higher doses.

this analysis was only based on cycle 1.
For the AP group (took XEOMIN injection in cycle 1), after comparing the difference between visit 1 (day 0) and visit 5(week 12, the start of 2 nd injection cycle) for all measures via paired t-test or paired Wilcoxon sign test (if normal assumptions are significantly violated),

, Elbox_Flex_avg) had significant difference between visit 1 and visit 5.
The reason maybe the drug still had effect at visit 5, so we could not take 2 cycles into analysis.
nd injection cycle) for all measures via paired ttest or paired Wilcoxon sign test (if normal assumptions are significantly violated), there were

Table 11 :
Secondary Efficacy Endpoint PSS: Perceived Stress Scale